Purine intermediates

ABSTRACT

Compounds of formula (II): ##STR1## wherein R 4  &#39; is R 4  wherein 
     R 4  is hydrogen, hydroxy, amino or OR 5  wherein 
     R 5  is C 1-6  alkyl, phenyl or phenyl C 1-2  alkyl either of which phenyl moieties may be substituted by one or two halo, C 1-4  alkyl or C 1-4  alkoxy groups; 
     or R 4  &#39; is a group or atom convertible to R 4  ; and 
     R x  is amino or protected amino; 
     which are useful intermediates in the preparation of purine derivatives having antiviral activity.

This is a continuation-in-part of copending application(s) Ser. No.260,456 filed on Oct. 20, 1988, now U.S. Pat. No. 4,910,307.

The present invention relates to novel intermediates for use in aprocess for the preparation of compounds having antiviral activity.

EP-A-0242482 describes a class of purine derivatives having antiviralactivity, and processes by which they may be prepared.

Novel intermediates have has now been discovered for the preparation ofthese compounds of formula (I) and pharmaceutically acceptable saltsthereof.

A process for the preparation of compounds of formula (I), andpharmaceutically acceptable salts thereof: ##STR2## wherein R₁ ishydrogen or CH₂ OH;

R₂ is hydrogen or, (when R₁ is hydrogen), hydroxy or CH₂ OH;

R₃ is CH₂ OH or, (when R₁ and R₂ are both hydrogen), CH(OH)CH₂ OH;

R₄ is hydrogen, hydroxy, amino or OR₅ wherein

R₅ is C₁₋₆ alkyl, phenyl or phenyl C₁₋₂ alkyl either of which phenylmoieties may be substituted by one or two halo, C₁₋₄ alkyl or C₁₋₄alkoxy groups;

and in which any OH groups in R₁ R₂ and/or R₃ may be in the form of0-acyl, phosphate, cyclic acetal or cyclic carbonate derivativesthereof;

comprises the reaction of a compound of formula (II): ##STR3## whereinR₄ ' is R₄ or a group or atom convertible thereto and R_(x) is amino orprotected amino; with a compound of formula (III):

    R.sub.3 'CHR.sub.2 'CHR.sub.1 'Q                           (III)

wherein Q is a leaving group and R₁ ', R₂ ' and R₃ are R₁ R₂ and R₃respectively or R₁, R₂ and/or R₃ wherein the OH group(s) is/are inprotected form; and thereafter converting R₄ ' when other than R₄, to anR₄ moiety or converting R₄ ' when R₄ to other R₄ ; if necessaryconverting R₁ ', R₂ ' or R₃ ' to R₁, R₁ and R₃ respectively andoptionally forming a pharmaceutically acceptable salt, O-acyl,phosphate, cyclic acetal or cyclic carbonate derivative thereof.

There are groups of compounds within formula (I) as follows:

(a) R₁ and R₂ are both hydrogen and R₃ is CH₂ OH, and derivativesthereof as defined;

(b) R₁ is hydrogen and R₂ and R₃ are both CH₂ OH, and derivativesthereof as defined;

(c) R₁ is hydrogen, R₂ is hydroxy and R₃ is CH₂ OH, and derivativesthereof as defined;

(d) R₁ is CH₂ OH, R₂ is hydrogen and R₃ is CH₂ OH, and derivativesthereof as defined.

(e) R₁ and R₂ are both hydrogen and R₃ is CH(OH)CH₂ OH, and derivativesthereof as defined.

Examples of R₅ include methyl, ethyl, n- and iso-propyl, phenyl andbenzyl optionally substituted by one or two or methyl, ethyl, n- andiso-propyl, methoxy, ethoxy, n- and iso- propoxy, fluoro, chloro, bromoor CF₃.

O-Acyl derivatives are normally those wherein one or more of OH groupsin R₁, R₂ and/or R₃ form carboxylic ester groups; such as C₁₋₇ alkanoyland benzoyl optionally substituted by one or two C₁₋₄ alkyl, C₁₋₄alkoxy, halogen or CF₃ groups. Preferably, carboxylic ester groups areC₁₋₇ alkanoyl groups, such as acetyl, propionyl, butyryl, heptanoyl andhexanoyl, most preferably acetyl or propionyl.

Examples of phosphate esters of the compounds of formula (I) includethose where one of the acyclic --OH groups is replaced by (HO)₂ --PO₂--groups or salts thereof, or where two --OH groups on carbon atoms arereplaced by a bridging --O--P(OH)O₂ --group.

When R₁, R₂ and R₃ together contain more than one OH group, cyclicacetal groups, such as --O--C(C₁₋₃ alkyl)₂ --O--or cyclic carbonate,such as --O--CO--O--may be formed.

Examples of pharmaceutically acceptable salts of the compound of formula(I) are acid addition salts formed with a pharmaceutically acceptableacid such as hydrochloric acid, orthophosphoric acid and sulphuric acid.Pharmaceutically acceptable salts also include those formed with organicbases, preferably with amines, such as ethanolamines or diamines; andalkali metals, such as sodium and potassium.

When the compound of formula (I) contains a phosphate group suitablesalts include metal salts, such as alkali metal salts, for examplesodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy-lower alkylaminessuch as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortris-(2-hydroxyethyl)-amine.

It will be appreciated that some of the compounds of formula (I) have atleast one asymmetric centre, and therefore are capable of existing inmore than one stereoisomeric form. The invention extends to each ofthese forms individually and to mixtures thereof, including racemates.The isomers may be separated conventionally by chromatographic methodsor using a resolving agent. Alternatively, the individual isomers may beprepared by asymmetric synthesis using chiral intermediates.

It will be further appreciated that, when R₄ is hydroxy in formula (I),the compound exists in the preferred tautomeric form of formula (IA):##STR4## The compounds of formula (I) including their alkali metal saltsmay form solvates such as hydrates and these are included wherever acompound of formula (I) or a salt thereof is herein referred to.

It will also be appreciated that compounds of formula (I) wherein R₄ isother than hydroxy are pro-drugs for the compounds of formula (I)wherein R₄ is hydroxy.

Suitable values for R_(x) include amino, when Q is other than hydroxy,or, when Q is hydroxy, R_(x) is protected amino, such as groups whichincrease the solubility of the molecule. Preferred examples includecarbamates such as ^(t) butyloxycarbonyl, and phthalimide.

Suitable values for Q in formula (III) include hydroxy, halo, such aschloro, bromo and iodo, preferably iodo; or other groups readilydisplaceable by nucleophile, such as mesyloxy and tosyloxy.

When Q is other than hydroxy, the reaction preferably takes place in aninert solvent, such as dimethylformamide in the presence of a base, suchas potassium carbonate, at 0° to 50° C., preferably at ambienttemperature.

When Q is hydroxy, the reaction values place in an inert solvent, suchas tetrahydrofuran in the presence of a condensation promoting agent,such as diethyl azodicarboxylate (DEAD) and triphenylphosphine at 0° to50° C., preferably at ambient temperature.

R₄ may often be an alkoxy group, such as methoxy, which may be convertedto R₄ is hydroxy by the methods of D. R. Haines, J. Med. Chem. 1987, 30,943 and K. K. Ogilvie and H. R. Hanna, Can. J. Chem. 1984, 62, 2702.

When R_(4') is chloro, it may be converted to R₄, as follows:

i) Hydrolysis to R₄ is hydroxy may be carried out using aqueous mineralacid, such as hydrochloric acid, or more preferably using an organicacid, such as formic acid at elevated temperature, suitably 70°-150° C.,preferably 100° C.

ii) Reduction to R₄ is hydrogen, preferably using catalytic methods,such as palladium on charcoal in an inert solvent, such as methanol orethanol at reflux temperatures. The hydrogen source may be cyclohexeneor ammonium formate. The procedure is analogous to of that described byT. A. Krenitsky et.al. Proc.Natl.Acad Sci. USA. 81, 3209 (1984).

iii) Conversion to R₄ is amino may be achieved conventionally bytreatment with ammonia in methanol in an autoclave at 100° C. for aperiod of about 7 hours, or alternatively, with sodium azide indimethylformamide to form an azido intermediate (wherein R₄ is N₃),followed by reduction of this intermediate with ammoniumformate/palladium on charcoal, in methanol.

iv) Reaction with OR₅ - with the resulting chloro compound may beachieved using, preferably, NaOR₅ in a suitable solvent, such asmethanol or ethanol when R₅ is methyl or ethyl respectively, at 0°-150°C., preferably around 50° C. The procedure is analogous to thatdescribed in Example 15 of EP-A-141927.

R₁ ', R₂ ' and/or R₃ ' when protected OH groups, the protecting group(s)are often hydrogenolysable such as a benzyl group optionally substitutedas defined above for R₅ when phenyl, also including nitro as an optionalsubstituent.

Removal of benzyl protecting groups may be achieved conventionally, bycatalytic hydrogenation using palladium on charcoal as catalyst (when R₄is other than hydrogen).

Other suitable protecting groups include substituted benzyl groups suchas p-methoxybenzyl, removable by treatment with DDQ.

Another suitable protecting group is the ^(t) Butyl dimethylsilyl groupremovable by 80% acetic acid at elevated temperatures, around 90° C., ortreatment with tetrabutyl ammonium fluoride in a solvent such astetrahydrofuran, at ambient temperature.

A particularly suitable protecting group is that wherein two OH groupson carbon atoms α- or β- to one another are reacted with2,2-dimethoxypropane, forming a 1,3-dioxolan or 1,3-dioxan ringrespectively. This group may be removed by acidic hydrolysis.

Alternative values for R₂ ' and R₃ ', when protected OH groups, includethat wherein two OH groups on adjacent carbon atoms are replaced by abond; for example, when R₁ is hydrogen, R₂ is hydroxy and R₃ is CH₂ OH;R₃ 'CHR₂ 'CHR₁ 'O-- is CH₂ ═CH--CH₂ --O--. The diol formation(`deprotection`) may be achieved conventionally, for example, usingosmium tetroxide, preferably catalytically in the presence ofN-methylmorpholine N-oxide.

Pharmaceutically acceptable salts, O-acyl derivatives and phosphatederivatives may be prepared conventionally, for example as described inEP-A-141927 and EP-A-182024.

Acyl derivatives of compounds of formula (I) may be prepared byacylating an optionally protected compound of formula (I) in accordancewith conventional acylating processes known in the art, and wherenecessary, deprotecting the resulting product.

The acylation reaction may be carried out by using an acylating agentcontaining a suitable carboxylic acid acyl group.

Examples of acylating agents suitable for the above process arecarboxylic acids, acid halides, such as chlorides or acid anhydrides,preferably anhydrides or acids.

When the acylating agent is a carboxylic acid, a condensation promotingagent such as dicyclohexylcarbodiimide should be included, but this isnot necessary when the acylating agent is an acid anhydride.

The acylation reaction may produce a single acyl derivative of acompound of formula (I), or a mixture of derivatives, depending on anumber of factors, such as the relative amounts and chemical natures ofreactants, the physical conditions of the reaction, and the solventsystem. Any mixture produced in this way may be separated into its purecomponents using standard chromatographic techniques.

The above described acylation process of the invention can yield mono-or di-acylated derivatives of compounds of formula (I) containing two OHgroups, according to the form of protection/deprotection utilised. Thefollowing are examples of products obtained by different methods:

(a) Acylated derivatives of the OH groups in R₁ /R₂ /R₃ when both acylgroups are the same, may be obtained by direct acylation of compounds offormula (I).

(b) Mono-acylated derivatives of one OH group when R₁, R₂ and R₃together contain two OH groups may be obtained by acylation of protectedintermediates of compounds of formula (I) in which the other --OH groupin R₁ /R₃ /R₃ is preferably protected by, for example, amonomethoxytrityl or trityl group, and subsequent deprotection by acidtreatment. Di-acylated derivatives wherein the acyl groups are differentmay then be prepared as in (a).

Acyl derivatives of the compounds of formula (I) can be converted to acompound of formula (I) by conventional deacylation or partialdeacylation processes. For example, reaction with methanolic ammonia canbe used to effect complete deacylation to yield a compound of formula(I) wherein both OH groups (when present) are deacylated. Reaction witha mild base such as potassium carbonate can result in partialdeacylation of a di-acylated derivative to produce a compound of formula(I) wherein one acyl group and one OH group are present.

Phosphate derivatives are formed by reaction with a phosphorylatingagent such as phosphorus oxychloride in pyridine. The NH₂ and any OHgroups in R₁, R₂ and/or R₃ are protected as desired or necessary,preferably using a trityl or methoxytrityl protecting group, removableby acid hydrolysis, using acetic acid.

When more than one OH group in R₁, R₂ and R₃ is phosphorylated, a cyclicphosphate derivative is produced with phosphorus oxychloride, when theOH groups are α or β to one another.

Another suitable phosphorylating agent is cyanoethyl phosphoric acid, inwhich case the product is normally treated with aqueous ammonia, whichyields the ammonium salt of the phosphate ester as the final product.

A monophosphate may be converted to a cyclic phosphate using adehydrating agent, such as dicyclohexylcarbodiimide.

Cyclic acetal derivatives of the compounds of formula (I) may beprepared from the compound of formula (I) wherein two OH groups in theside chain are present, preferably β- to one another, using an acyclicacetal, such as R₁₀ O--C(C₁₋₃ alkyl)2--OR₁₀ wherein R₁₀ is C₁₋₄ alkyl,such as methyl or ethyl. The reaction is preferably carried out in aninert solvent such as tetrahydrofuran or dimethylformamide in thepresence of an acid such as p-toluenesulphonic acid.

Cyclic carbonate derivatives of the compounds of formula (I) may beprepared from the compound of formula (I), wherein the --NH₂ group ispreferably protected; with phosgene or 1,1-carbonyldimidazole, andthereafter deprotecting where necessary. Suitable protecting groupsinclude trityl and monomethoxytrityl. The reaction is preferably carriedout in dry pyridine at 0°-50° C., preferably at ambient temperature.

It will be appreciated that conversions of R₄, deprotections andderivative formations may take place in any desired or necessary order.

Accordingly, the present invention provides intermediates of formula(II) as hereinbefore defined.

Compounds of the formula (II) wherein R₄ ' is chloro may be prepared bythe reaction of a compound of formula (IV): ##STR5## wherein R₆ isformyl, and Y is a protecting group, with diethoxymethyl acetate, givinga compound of formula (V): ##STR6## followed by removal of R₆,deprotection of Y and if desired or necessary, converting the 2-aminogroup to R_(x) when protected amino and/or converting the chlorosubstituent to other R₄ '.

Suitable values for Y include benzyl, removable by hydrogenation and thetetrahydropyran-2-yl group, removable by treatment with 80% acetic acid,at ambient temperature.

It will be appreciated that the subsequent conversions may take place inany desired or necessary order.

In one aspect, the chloro group is first converted to R₄ ' is methoxy,by treatment with methoxide ion (see process iv) as hereinbeforedescribed), then Y, preferably benzyl, is removed.

Compounds of the formula (IV) may be prepared by the reaction of acompound of formula (VI): ##STR7## with YONH₂ in an inert solvent, suchas dioxan or diglyme in the presence of an acid acceptor, such astriethylamine or diisopropylethylamine.

The above methods are as described in the Examples hereinafter.

Intermediates of the formula (III) are known or prepared by methodsanalogous to those used for the preparation of structurally similarknown compounds.

The compound of formula (VI) wherein R₆ is formyl may be prepared byreaction of the corresponding compound of formula (VI) wherein R₆ ishydrogen with formic acid and acetic anhydride.

The compound of formula (VI) wherein R₆ is hydrogen,2,5-diamino-4,6-dichloropyrimidine is a known compound as described inC. Temple, Jr, B. H. Smith and J. A. Montgomery, J. Org. Chem., 40 (21),3141, 1975.

The following Examples illustrate the preparation of compounds offormula (I). Examples 1d), 2b) and 3c) describe the preparation ofintermediates of the invention.

EXAMPLE 1 a) 6-Benzyloxyamino-4-chloro-2,5-diformamido-pyrimidine

A mixture of 4,6-dichloro-2,5-diformamido-pyrimidine (1.9g, 8.09mmol),benzyloxyamine (1g, 8.13mmol), triethylamine (2ml) and dioxan (20ml) wasstirred at 100° C. for 1 hour. The cooled reaction mixture was filteredand the precipitate collected and washed with dioxan (2×5ml). Thefiltrate and washings were combined and evaporated to a syrup. Columnchromatography on silica gel (eluted with chloroform-ethanol, 30:1)afforded the title compound (1.2g, 46%). IR: υ_(max) (KBr) 3242, 1694,1588, 1472cm⁻¹ ; ¹ H NMR δ_(H) [(CD₃)₂ SO], 4.89 (2H, s, OCH₂ Ph), 7.4(5H, m, Ph), 8.15 (1H, s, CHO), 9.18, 9.42 (1H, 2×br.s, D₂ Oexchangeable, NH), 9.25 (1H, br.s, CHO), 10.91 (2H, br.s, D₂ Oexchangeable, 2×NH). m/e (FAB +ve ion, thioglycerol) MH⁺ 322.

b) 9-Benzyloxy-6-chloro-2-formamidopurine

6-Benzyloxyamino-4-chloro-2,5-diformamidopyrimidine (1.2g, 3.73mmol) anddiethoxymethyl acetate (20ml) was stirred at 120° C. for 2.5 hours,cooled and evaporated under reduced pressure. The residue in methanol(20ml) and concentrated ammonia solution (2ml) was stirred at 20° C. for1 hour, the solvent removed under reduced pressure and the residueco-evaporated with methanol. Column chromatography on silica gel (elutedwith chloroform-ethanol, 100:1) afforded the title compound (700mg,62%). IR: υ_(max) (KBr) 3119, 1702, 1611, 1577, 1505, 1440cm⁻¹ ; ¹ HNMR: δ_(H) [(CD₃)₂ SO], 5.44 (2H, s, CH₂ Ph), 7.45 (5H, m, Ph), 8.54(1H, s, H-8), 9.34 (1H, s, CHO), 11.30 (1H, br.s, D₂ O exchangeable,NH). Found: C, 49.99; H, 3.37; N, 22.43%, m/e 303.0523. C₁₃ H₁₀ N₅ O₂Cl + 0.5 H₂ O requires: C, 49.92; H, 3.55; N, 22.40%, m/e 303.0520.

c) 2-Amino-9-benzyloxy-6-methoxypurine

A mixture of 9-benzyloxy-6-chloro-2-formamidopurine (440mg, 1.60mmol),1.2M sodium methoxide in methanol (5.3ml) and methanol (10ml) was heatedat reflux temperature for 1 hour and then cooled. Acetic acid (4ml) wasadded and the solution evaporated to dryness. The residue was suspendedin water and extracted with chloroform (2×25ml). The combined chloroformextracts were washed with brine, dried (magnesium sulphate) andevaporated under reduced pressure. Column chromatography on silica gel(eluted with chloroform-methanol, 100:1) afforded the title compound(331mg, 76%). IR: υ_(max) (KBr) 3480, 3310, 1625, 1585, 1505, 1485,1460, 1400cm⁻¹ ; ¹ H NMR: δ_(H) [(CD₃)₂ SO] 3.96 (3H, s, CH₃), 5.31 (2H,s, CH₂ Ph), 6.64 (2H, br.s, D₂ O exchangeable, NH₂), 7.42 (5H, s, Ph),7.75 (1H, s, H-8). Found: C, 57.18, H, 4.84; N, 25.85%). m/e 271.1075.C₁₃ H₁₃ N₅ O₂ requires: C, 57.56, H, 4.83, N, 25.82%; m/e 271.1069.

d) 2-Amino-9-hydroxy-6-methoxypurine

A mixture of 2-amino-9-benzyloxy-6-methoxypurine (300mg, 1.11mmol), 10%palladium-on-charcoal (100mg), ethanol (10ml) and dioxan (5ml) wasstirred under an atmosphere of hydrogen for 45 minutes. The catalyst wasthen removed and the filtrate evaporated to a white solid2-amino-9-hydroxy-6-methoxypurine (190mg, 95%). IR: υ_(max) (KBr) 3312,1643, 1591, 1394cm⁻¹ ; ¹ H NMR: δ_(H) [(CD₃)₂ SO] 3.95 (3H, s, CH₃),6.45 (2H, br.s, D₂ O exchangeable, NH₂), 7.93 (1H, s, H-8), 11.75 (1H,br.s, OH). Found: m/e 181.0594. C₆ H₇ N₅ O₂ requires: m/e 181.0596.

e) 2-Amino-9-(2,2-dimethyl-1,3-dioxan-5-ylmethoxy)-6-methoxypurine

A mixture of 2-amino-9-hydroxy-6-methoxypurine (50mg, 0.276mmol),2,2-dimethyl-5-iodo-methyl-1,3-dioxan (70.6mg, 0.276mmol), potassiumcarbonate (40.1mg, 0.290mmol) and dimethylformamide (1ml) was stirred at20° C. for 3 hours. The suspension was diluted with chloroform (2ml),filtered and the filtrate evaporated to dryness. The residue waschromatographed on silica gel (eluted with chloroform-ethanol, 100:1)yielding the title compound (59.6mg, 70%). IR: υ_(max) (KBr) 3396, 1640,1581, 1480, 1390cm⁻¹ ; ¹ H NMR: δ_(H) [(CD₃)₂ SO] 1.32 (3H, s, CH₃),1.35 (3H, s, CH₃), 2.00 (1H, m, CH), 3.77 (2H, dd, J=11.8, 6.1 Hz,2×H.sub.(ax)), 3.96 (3H, s, OCH₃), 3.99 (2H, dd, J=11.8, 4.1 Hz,2×H(eq)), 4.36 (2H, d, J=6.8 Hz, CH₂ ON), 6.60 (2H, br.s, D₂ Oexchangeable, NH₂), 8.14 (1H, s, H-8). Found: C, 50.67; H, 6.31; N,22.00%; m/e 309.1425. C₁₃ H₁₉ N₅ O₄ + 0.2 EtOH requires: C, 50.53; H,6.41; N, 21.99%; m/e 309.1434.

This compound may be converted to the corresponding compound of formula(I) wherein R₄ is hydroxy according to the methods thereinbeforedescribed. Conversion to R₂ and R₃ are CH₂ OH may be achieved byconventional hydrolysis.

EXAMPLE 2 a) 9-Benzyloxy-2-[(bis-t-butoxycarbonyl)amino]-6-methoxypurine

A solution of 2-amino-9-benzyloxy-6-methoxypurine (0.47g; 1.73mmol),di-t-butyldicarbonate (0.57g; 2.60mmol) and 4-N,N-dimethylaminopyridine(100mg, 0.173mmol) in tetrahydrofuran was heated at reflux for 45minutes. Additional di-t-butyldicarbonate (0.20g) was then added and thesolution refluxed for 30 minutes. The reaction was then cooled and thesolvent removed under reduced pressure. The residue was purified bycolumn chormatography on silica gel eluting with chloroform-methanolmixtures, affording the title compound (740mg; 91%). IR: υmax (KBr)3110, 2990, 1760, 1600, 1485, 1460, 1400 cm⁻¹ ; ¹ H NMR: δH(CDCl₃)1.50(18H, s, 6×CH₃), 4.15(3H, s, CH₃), 5.45(2H, s, CH₂), 7.35(5H, s,Ar), 7.65(1H, s, H-8).

b) 2-[(Bis-t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine

A mixture of9-benzyloxy-2-[(bis-t-butoxycarbonyl)-amino]-6-methoxypurine (990mg;2.10mmol), 10% palladium on charcoal (100mg), ethanol (25ml) and dioxan(25ml) was stirred at 20° C. under an atmosphere of hydrogen for 45minutes. The suspension was then filtered and the filtrate evaporatedunder reduced pressure. The resulting white solid was dried to yield thetitle compound (760mg; 95%). IR: υmax (KBr) 2990, 2420, 1760, 1740,1730. 1710. 1605. 1480 cm⁻¹ ; ¹ H NMR δH[(CD₃)₂ SO] 1.40(18H, s, 6×CH₃),4.05(3H, s, OCH₃), 8.05(1H, s, H-8), 11.8(1H, br.s, D₂ O exchangeable,OH). Found: C, 50.27; H, 6.12; N, 17.70%. C₁₆ H₂₃ N₅ O₆ + 0.2EtOHrequires: C, 50.42; H, 6.23; N, 17.66%.

c)2-(Bis-t-butoxycarbonyl)amino1-9-(3-t-butyldimethylsilyloxyprop-1-oxy)-6-methoxypurine

Diethyl azodicarboxylate (0.62ml; 3.93mmol) was added to a solution of2-[(bis-t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine (1.0g;2.62mmol), 3-t-butyl-dimethylsilyloxypropan-1-ol (0.5g: 2.62mmol) andtriphenylphosphine (1.03g; 3.93mmol) in tetrahydrofuran (20ml) at 0° C.After 5 minutes at 0° C. the solution was allowed to warm to 20° C. andstirred for a further 2 hours. The solvent was then removed underreduced pressure, and the residue purified by column chromatography onsilica gel eluting with hexaneacetone (3:1), affording the titlecompound (1.3g, 89%). IR: υmax (film) 2940, 2965, 1795, 1760, 1600,1475, 1395 cm⁻¹ ; ¹ H NMR δ_(H) [(CD₃)₂ SO] 0.04(6 H, s, 2×CH₃),0.85(9H, s, 3×CH₃), 1.40(18H, s, 6×CH₃), 1.90(2H, quintet, J= 6.1,6.3Hz, CH₂ CH₂ CH₂), 3.78(2H, t, J=6.1Hz, CH₂ OSi), 4.08(3H, s, CH₃),4.48(2H, t, J=6.3Hz, CH₂ ON), 8.74(1H, s, H-8). Found: m/e 554.2993. C₂₅H₄₄ N₅ O₇ Si requires: m/e 554.3010.

d) 9-(3-Hydroxyprop-1-oxy)quanine

A solution of2-[(bis-t-butoxycarbonyl)amino]-9-(3-t-butyldimethylsilyloxyprop-1-oxy)-6-methoxypurine(1.1g; 1.99mmol) and 5N hydrochloric acid (1.19ml) in ethanol (10ml) washeated at reflux for 5 hours. The reaction was cooled, evaporated underreduced pressure and the residue co-evaporated with ethanol (x4). Theresidue was suspended in ethanol-water (1:1; 10ml) and concentratedaqueous ammonia was added until dissolution had occurred. The solutionwas filtered and the filtrate left to stand unstoppered to allow theammonia to evaporate. After 48 hours the resulting solid was collected,washed with water, ethanol and dried to afford the title compound(220mg; 50%). IR υmax (KBr) 3190, 1720, 1685, 1630, 1605 and 1475 cm⁻¹ ;¹ H NMR δH[(CD₃)₂ SO] 1.80(2H, quintet, J=6.3Hz, CH₂ CH₂ CH₂), 3.55(2H,quartet, J=5.5, 6.3Hz, CH₂ OH), 4.32(2H, t, J=6.3Hz, CH₂ ON), 4.57(1H,t, J=5.5Hz, D₂ O exchangeable, OH), 6.57(2H, br. s, D₂ O exchangeable,NH₂), 7.91(1H, s, H-8), 10.63(1H, br. s, D₂ O exchangeable, H-1). Found:C, 41.33; H, 5.20; N, 30.24%. C₈ H₁₁ N₅ O₃.O.4H₂ O requires: C, 41.33;H, 5.13; N, 30.14%.

EXAMPLE 3 a) 2-Amino-9-benzyloxy-6-chloropurine

A solution of 9-benzyloxy-6-chloro-2-formamidopurine (3.0g; 9.88mmol) in0.05M sodium ethoxide in ethanol was heated at reflux temperature for11/2h and then cooled. Acetic acid (0.5ml) was then added and thesolvent removed under vacuo. The residue was purified by columnchromatography eluting with chloroform: methanol (50:1) to afford thetitle compound (2.0g; 73%). υ_(max) (KBr) 3397, 3312, 3205, 1634, 1558,1505, and 1468cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 5.45 (2H, s, CH₂ Ar), 7.20 (2H,br.s, D₂ O exchangeable, NH₂), 7.50 (5H, s, Ph), 8.15 (1H, s, H-8).(Found: C, 52.74; H, 3.70; N, 25.62%, C₁₂ H₁₀ N₅ OCl requires: C, 52.27;H, 3.66; N, 25.41%).

b) 9-Benzyloxy-2-(bis-t-butoxycarbonyl)amino1-6-chloropurine

Di-t-butyldicarbonate (7.94g; 36.2mmol) was added portionwise over 1h toa solution of 2-amino-9-benzyloxy-6-chloropurine (6.73g; 24.4mmol) and4-N, N-dimethylaminopyridine (600mg; 1.04mmol) in tetrahydrofuran at 20°C. Further quantities of di-t-butyldicarbonate was added portionwiseuntil the reaction had gone to completion. The solution was filteredthrough a bed of silica gel and then the silica washed withtetrahydrofuran. The combined filtrates were evaporated under vacuo andthe residue purified by column chromatography eluting with hexane:acetone (3:1) to give the title compound (7.83g; 67%). υ_(max) (KBr)2978, 1740, 1710, 1562, 1368, and 1352cm⁻¹ ; δ_(H) (CDCl₃) 1.55 (18H, s,6CH₃), 5.50 (2H, s, CH₂ Ar), 7.45 (5H, m, Ph), 7.80 (1H, s, H-8).(Found: C, 55.99; H, 5.57; N, 14.75%; C₂₂ H₂₆ N₅ O₅ Cl requires: C,55.51; H, 5.52; N, 14.72%).

c) 2-[(Bis-t-butoxycarbonyl)amino]-6-chloro-9-hydroxypurine

A mixture of 9-benzyloxy-2-[(bis-t-butoxycarbonyl)amino]-6-chloropurine(7.50g; 13.7mmol), 5% palladium on charcoal (1650mg) and tetrahydrofuran(100ml) was stirred at 20° C. under an atmosphere of hydrogen for 11/2h.The suspension was then filtered and the catalyst washed with ethanol.The combined filtrates were evaporated to afford a white solid of thetitle compound (6.3g; 100%). υ_(max) (KBr) 2980, 2536, 1779, 1743, 1706,1567, 1394, and 1370cm⁻¹ ; δ_(H) [(CD₃)₂ SO]1.41 (18H, s, 6CH₃), 8.94(1H, s, H-8), and 12.80 (1H, br.s, D₂ O exchangeable, N-OH). (Found: C,46.98; H, 5 35; N, 17.78%; C₁₅ H₂₀ N₅ O₅ Cl requires: C, 46.69; H, 5.24;N, 18.15%).

d)2-(Bis-t-butoxycarbonyl)amino]-9-[3-(t-butyldimethylsiloxy)propoxy]-6-chloropurine

Diethyl azodicarboxylate (0.31ml; 1.95mmol) was added dropwise withstirring to a solution of2-[(bis-t-butoxycarbonyl)amino]-6-chloro-9hydroxypurine,3-(t-butyldimethylsiloxy)propanol (0.25g; 1.30mmol) andtriphenylphosphine (0.51g; 1.95mmol) in tetrahydrofuran at O° C. Thesolution was allowed to warm to 20° C. and stirred for 11/2h. Thesolvent was then removed and the residue purified by columnchromatography on silica gel eluting with hexane: acetone (3:1) toafford the title compound (580mg; 80%). υ_(max) (KBr) 2955, 1733, 1670,1565, and 1367cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 0.04 (6H, s, 2CH₃), 0.86 (9H, s,3CH₃), 1.41 (18H, s, 6CH₃), 1.92 (2H, quintet, J6.3Hz, CH₂ CH₂ CH₂),3.78 (2H, t, J6.3Hz, CH₂ OSi), 4.54 (2H, t, J6.3Hz, CH₂ ON), 9.09 (1H,s, H-8). (Found: C, 51.65; H, 6.90; N, 12.37%; C₂₄ H₄₀ N₅ O₆ ClSirequires: C, 51.63; H, 7.24; N, 12.55%).

e) 9-(3-Hydroxypropoxy)quanine

A solution of2-[(bis-t-butoxycarbonyl)amino]-9-[3-(t-butyldimethylsilyloxy)propoxy]-6-chloropurine(500mg; 0.90mmol) in 80% formic acid (10ml) was heated at 100° C. for2h. The solution was then cooled, evaporated to dryness and the residueco-evaporated with water (×2). The residue was dissolved in concentratedaqueous ammonia and left at 20° C. for 1/2h. The solvent was thenremoved and the residue recrystallised from water to afford the titlecompound (121mg; 60%). υ_(max) (KBr) 3190 1720, 1685, 1630, 1605, and1475cm⁻¹ ; δ_(H) [(CD₃)₂ SO] 1.80 (2H, quintet, J6.0, 6.6Hz, CH₂ CH₂CH₂), 3.55 (2H, quartet, J5.5, 6.0Hz, CH₂ OH), 4.32 (2H, t, J6.6Hz, CH₂ON), 4.57 (1H, t, J5.5Hz, D₂ O exchangeable, OH), 6.57 (2 H, s, D₂ Oexchangeable, NH₂), 7.91 (1H, s, H-8), and 10.63 (1H, s, D₂ Oexchangeable, NH).

I claim:
 1. A compound of formula (II) for use in the preparation ofcompounds having antiviral activity: ##STR8## wherein R₄ ' chloro or OR₅whereinR₅ is C₁₋₆ alkyl, phenyl or phenyl C₁₋₂ alkyl either or whichphenyl moieties may be substituted by one or two halo, C₁₋₄ alkyl orC₁₋₄ alkoxy groups; and R_(x) is amino, t-butyloxycarbonylamino,phthalimido or formylamino.
 2. A compound according to claim 1 whereinR₄ ' is chloro.
 3. 2-Amino-9-hydroxy-6-methoxypurine or2-[(bis-t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine. 4.2-Amino-9-hydroxy-6-chloropurine or2-[(bis-t-butoxycarbonyl)amino]-9-hydroxy-6-chloropurine.